REGN5381 in Adult Participants With Heart Failure With Reduced Ejection Fraction

Key Inclusion Criteria

1. Body mass index (BMI) between 18 and 45 kg/m2, inclusive, at initial screening visit

2. Diagnosis of chronic heart failure

3. Left ventricular ejection fraction 20-49% by echocardiogram performed within 3 months of screening

4. Plasma NT-proBNP ≥800 pg/mL (or ≥1000 pg/mL if in atrial fibrillation) at screening (visit 1) and NT-proBNP ≥600 pg/mL (or ≥800 pg/mL if in atrial fibrillation) approximately 30 days prior to randomization (visit 5)

5. Receiving optimized standard of care therapy for heart failure as described in the protocol

6. Sacubitril-valsartan cohort only: treatment with sacubitril-valsartan at screening and at baseline

7. Low eGFR cohort only: eGFR of 30-45 mL/min/1.73 m2 at screening and within approximately 30 days of randomization

Key Exclusion Criteria

1. Hospital discharge within 180 days of anticipated randomization

2. Resting SBP that remains out of range after two repeated measurements prior to randomization as described in the protocol

3. Estimated glomerular filtration rate (eGFR) of <45 mL/min/1.73 m2 according to locally used formula (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] preferred), at screening (eGFR of 30-45 mL/min/1.73 m2 required for participants in the low eGFR cohort)

4. Current or recent diagnosis of acute coronary syndrome or myocardial infarction as described in the protocol

5. History of symptomatic autonomic dysfunction as evidenced by orthostatic hypotension and/or syncope

6. Unexplained syncope <12 months prior to initial screening or during the Run-in period

7. History of clinically significant cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, psychiatric, or neurological disease, as assessed by the investigator that may confer unreasonable risk to the participant's participation in the study

8. Uncorrected congenital heart disease

9. Cardiac surgery within 6 months prior to screening or any planned surgery during the study

10. Implantation of a cardiac resynchronization therapy device in the prior 90 days, or planned during the study, or planned device optimization 30 days prior to randomization or during the study

11. Current chronic lung disease requiring long-term oxygen therapy

Note: Other protocol-defined inclusion/ exclusion criteria apply